text: Membranes play a twofold role for catecholamines: catecholamines must pass through membranes and deliver their chemical message at membrane receptors.
  Catecholamines are synthesized inside cells and sequestered in intracellular vesicles. This was first shown by Blaschko and Arnold Welch (1908–2003) in Oxford and by Hillarp and his group in Lund for the adrenal medulla and later for sympathetic nerves and the brain. In addition the vesicles contained adenosine triphosphate (ATP), with a molar noradrenaline:ATP ratio in sympathetic nerve vesicles of 5.2:1 as determined by Hans-Joachim Schümann (1919–1998) and Horst Grobecker (born 1934) in Peter Holtz′ group at the Goethe University Frankfurt. Blaschko and Welch wondered how the catecholamines got out when nervous impulses reached the cells. Exocytosis was not among the possibilities they considered. It required the analogy of the ″quantal″ release of acetylcholine at the neuromuscular junction shown by Bernard Katz, third winner of the 1970 Nobel Prize in Physiology or Medicine; the demonstration of the co-release with catecholamines of other vesicle constituents such as ATP and dopamine β-hydroxylase; and the unquestionable electron microscopic images of vesicles fusing with the cell membrane – to establish exocytosis.
  Acetylcholine, once released, is degraded in the extracellular space by acetylcholinesterase, which faces that space. In the case the catecholamines, however, the enzymes of degradation monoamine oxidase and catechol-O-methyl transferase, like the enzymes of synthesis, are intracellular. Not metabolism but uptake through cell membranes therefore is the primary means of their clearance from the extracellular space. The mechanisms were deciphered beginning in 1959. Axelrods group in Bethesda wished to clarify the in vivo fate of catecholamines using radioactively labelled catecholamines of high specific activity, which had just become available. H-adrenaline and H-noradrenaline given intravenously to cats were partly O-methylated, but another part was taken up in the tissues and stored unchanged. Erich Muscholl (born 1926) in Mainz, who had worked with Marthe Vogt in Edinburgh, wished to know how cocaine sensitized tissues to catecholamines – a fundamental mechanism of action of cocaine discovered by Otto Loewi and Alfred Fröhlich in 1910 in Vienna. Intravenous noradrenaline was taken up into the heart and spleen of rats, and cocaine prevented the uptake, ″thus increasing the amount of noradrenaline available for combination with the adrenergic receptors″. The uptake of H-noradrenaline was severely impaired after sympathectomy, indicating that it occurred mainly into sympathetic nerve terminals. In support of this, Axelrod and Georg Hertting (born 1925) showed that freshly incorporated H-noradrenaline was re-released from the cat spleen when the sympathetic nerves were stimulated. A few years later, Leslie Iversen (born 1937) in Cambridge found that other cells also took up catecholamines. He called uptake into noradrenergic neurons, which were cocaine-sensitive, uptake and uptake into other cells, which were cocaine-resistant, uptake. With the reserpine-sensitive uptake from the cytoplasm into the storage vesicles there were thus three catecholamine membrane passage mechanisms. Iversens book of 1967 “The Uptake and Storage of Noradrenaline in Sympathetic Nerves” was successful, showing the fascination of the field and its rich pharmacology.
  With the advent of molecular genetics, the three transport mechanisms have been traced to the proteins and their genes since 1990. They now consist of the plasma membrane noradrenaline transporter (NAT or NET), the classical uptake, and the analogous dopamine transporter (DAT); the plasma membrane extraneuronal monoamine transporter or organic cation transporter 3 (EMT or SLC22A3), Iversens uptake; and the vesicular monoamine transporter (VMAT) with two isoforms. Transporters and intracellular enzymes such as monoamine oxidase operating in series constitute what the pharmacologist Ullrich Trendelenburg at the University of Würzburg called metabolizing systems'.